Elucidating Conformation and Hydrogen-Bonding Motifs of Reactive Thiourea Intermediates

Substituted diphenylthioureas (DPTUs) are efficient hydrogen-bonding organo-catalysts, and substitution of DPTUs has been shown to greatly affect catalytic activity. Yet, both the conformation of DPTUs in solution and the conformation and hydrogen-bonded motifs within catalytically active intermediates, pertinent to their mode of activation, have remained elusive. By combining linear and ultrafast vibrational spectroscopy with spectroscopic simulations and calculations, we show that different conformational states of thioureas give rise to distinctively different N–H stretching bands in the infrared spectra. In the absence of hydrogen-bond-accepting substrates, we show that vibrational structure and dynamics are highly sensitive to the substitution of DPTUs with CF3 groups and to the interaction with the solvent environment, allowing for disentangling the different conformational states. In contrast to bare diphenylthiourea (0CF-DPTU), we find the catalytically superior CF3-substituted DPTU (4CF-DPTU) to favor the trans–trans conformation in solution, allowing for donating two hydrogen bonds to the reactive substrate. In the presence of a prototypical substrate, DPTUs in trans–trans conformation hydrogen bond to the substrate’s C=O group, as evidenced by a red-shift of the N–H vibration. Yet, our time-resolved infrared experiments indicate that only one N–H group forms a strong hydrogen bond to the carbonyl moiety, while thiourea’s second N–H group only weakly interacts with the substrate. Our data indicate that hydrogen-bond exchange between these N–H groups occurs on the timescale of a few picoseconds for 0CF-DPTU and is significantly accelerated upon CF3 substitution. Our results highlight the subtle interplay between conformational equilibria, bonding states, and bonding lifetimes in reactive intermediates in thiourea catalysis, which help rationalize their catalytic activity.


N-D stretching bands of DPTUs in dichloromethane
In the main text we show the N-H stretching bands for 0CF-DPTU and 4CF-DPTU together with the spectra for isotopically substituted DPTUs. The corresponding N-D stretching bands for the isotopically substituted 4CF-DPTU (shown with a scaled frequency axis in Figure S1a), is substantially more structured, with a double peak centered at ~2500 cm -1 (scaled ~3430 cm -1 ) and a red-shifted weaker band at ~2480 cm -1 (scaled ~3400 cm -1 ). For 0CF-DPTU two N-D bands at ~2475 cm -1 (scaled ~3390 cm -1 ) and ~2530 cm -1 (scaled ~3460 cm -1 ) are present, yet with an opposite intensity ratio as compared to the corresponding N-H bands ( Figure S1b). This different vibrational structure at N-D frequencies may indicate that coupling/conformational equilibria can be better disentangled for the N-D stretching modes due to different linewidths and the different intensities may point towards nuclear quantum effects. Yet, also Fermi resonances could give rise to a different vibrational structure (e.g. the shoulder in Figure S1a) and the exact intensity ratios of the two bands in Figures S1 & 2a somewhat depend on the subtraction of the solvent background. As such, we refrain from detailed analysis of the N-D stretching bands.

Spectral resolution of the transient signals of 0CF-DPTU
All fs-IR spectra shown in the main manuscript were recorded with a ~15 cm -1 spectral resolution to cover all transient spectral signatures (excited state absorption and ground state bleaching signal of all N-H modes), which however does not allow for spectrally resolving the two bands of 0CF-DPTU (see Figure 2, main manuscript). In Figure S2 we demonstrate that the two bands can be resolved using a higher spectral resolution, yet at the cost of detecting the other spectral features. The faster decay of the red-sifted band as compared to the blue-shifted band is also apparent from these data.

Kinetic modelling
To fit the transient absorption data ∆ ( , ), we use kinetic models based on two or three independently decaying populations of excited states ( Figure S3), which decay to a common, heated ground state. 1,2 Each state is characterized by its time-independent transient spectrum ( ), and the time-dependent populations of the excited states are assumed to decay with first order kinetics: The initial populations 0 correspond to the relative population of the excited states right after excitation. The heated ground state, which models weak transient signals (spectral shifts) due to dissipation of the vibrational excess energy, is populated as the vibrational relaxation progresses:

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[mOD] The measured isotropic spectra are modelled by a linear combination of the time dependent population of the three/four states multiplied by their corresponding spectra ( ): The thus extracted spectra of the different contributing spectral components are displayed in Figures 5b, 6b, 8c, and 9c of the main manuscript and the corresponding relaxation times, , are discussed in the main text.
We note that if the transition dipole moments of all molecular-level excited states are the same, the magnitude of ( ) associated excited states must be comparable. As such, we adjust the initial excited state populations 0 such that the maximum bleaching signals of the corresponding ( ) are the same. Therefore, the relative populations, as discussed in the main text, can be related to the relative abundance of the molecularlevel species (N-H conformation). We note that the assumption of similar transition dipole moments, , likely holds for the (non-hydrogen-bonded) cis and trans N-H groups of 4CF-DPTU and 0CF-DPTU: For water, the empirically determined transition dipole moment of the OH stretching vibration varies by < 5 % in the frequency range 3370-3400 cm -1 . 3 Assuming the same variation for the N-H stretching mode, we estimate the relative uncertainty in the ratio of the 4 values of the cis and trans N-H groups to < 20 % (due the ( )~( ) 4 sensitivity of the fs-IR experiment). Using error propagation, we thus estimate the uncertainty in the populations determined from the fs-IR experiment, which are also given in the main manuscript: The population of the trans N-H groups of the cis-trans conformer of 0CF-DPTU is estimated to 50 ± 5 %. For 4CF-DPTU the population of the trans conformer is accordingly estimated to 80 ± 3 %. The transition dipole moments can, however, be markedly enhanced upon hydrogen-bonding. 3 We therefore refrain from discussing these populations for experiments in the presence of DPP.

Hydrogen-bonding in 0CF-DPTU -DPP complexes from DFT calculations
In the main manuscript, our fs-IR data provide evidence for largely differing hydrogenbonding strengths of the two N-H groups of 0CF-DPTU in 0CF-DPTU -DPP complexes. This asymmetry in the hydrogen-bonding strengths is supported by density functional theory calculations of a 0CF-DPTU -DPP complex using the dispersion corrected revPBE functional in dichloromethane as a continuum solvent (see methods section of the main manuscript). Geometry optimization starting from 0CF-DPTU in trans-trans conformation, hydrogen-bonded to the C=O group of DPP results in two very dissimilar N-H ··· O distances (d1 = 2.10 Å and d2 = 2.59 Å, Figure S4a). The relative energy as a function of d2, which we determined from a relaxed energy scan upon constraining d2 at 2.70 Å to 1.80 Å at increments of 0.10 Å starting from the optimized geometry, and from an optimized geometry with short d2 and gradually shortening d1, indeed indicates that formation of a hydrogen-bond to only one N-H group is energetically favorable ( Figure  S4b). This asymmetry of both N-H hydrogen-bonds in the 0CF-DPTU:DPP complex can be explained by π-π interactions of the phenyl rings of DPP and 0CF-DPTU ( Figure  S4a). In fact, optimizing the geometry of a 0CF-DPTUacetone complex, where π-π interactions are absent, results in rather similar O-H hydrogen-bonding distances (d1 = 2.04 Å and d2 = 2.18 Å, Figure S4c).

Femtosecond infrared data for 4CF-DPTU:DPP at a 1:20 molar ratio
For better comparability of the two thioureas, we use mixtures with similar infrared absorbance in the main text. For 4CF-DPTU equimolar mixtures are presented in Figure 9 of the main manuscript. To better illustrate the asymmetry of the transient infrared spectra associated to the 4CF-DPTU -DPP complexes, we show in Figures S5 transient data for a mixture with a molar excess of DPP (1:20), for which the signatures of the 4CF-DPTU -DPP complexes prevail (Figure 7 in main text, see also Ref. 4 ). As can be seen from the data in Figure S5, which were recorded with a higher spectral resolution, the transient spectra display the asymmetric line shape at all times ( Figure  S5a). The rapidly decaying component (due to the 4CF-DPTU -DPP complexes) dominates the decay of the signal, only at blue-shifted frequencies (3373 cm -1 in Figure  S5c), where the contribution of the free thiourea is observed ( Figure 6 of the main manuscript), the signals decay more slowly at > 4 ps. The same two state kinetic model as used for the equimolar mixture ( Figure 9) describes the data very well, and the extracted spectra of the rapidly decaying component (0.8 ps decay time, orange line in Figure S5b) and of the slowly decaying component (6.4 ps decay time, green line in Figure S5b) excellently agree with the spectra found for the equimolar mixture ( Figure  9, main manuscript).